Translating the glutamatergic hypothesis of schizophrenia through homeostatic regulation of brain glycine

Sylvain Dubroqua, Philipp Singer, Kay Yan Benjamin Yee

Research output: Chapter in book / Conference proceedingChapter in an edited book (as author)Academic researchpeer-review

Abstract

No effective treatment exists for the negative symptoms and cognitive impairments of schizophrenia. The loss of normal affective and cognitive function severely undermines a patients’ ability to regain independence and social reintegration even when the positive psychotic symptoms have been stabilized by medications that are currently available. The US Food and Drug Administration fully recognizes the need and legitimacy to target negative and cognitive symptoms in drug development. The theoretical consensus that the pathogenesis of these symptoms involves glutamatergic N-methyl-d-aspartate (NMDA) receptor hypofunction has been driving for over three decades the impetus behind the search for feasible pharmacological strategies to improve NMDA receptor function. One promising approach that emerged in recent years is up-regulating brain glycine levels through the blockade of glycine transporter 1 (GlyT1). It is hypothesized that increasing the availability of glycine, the obligatory NMDA receptor co-agonist, near glutamatergic synapses can boost NMDA receptor excitability without the risk of excitotoxicity following direct stimulation of NMDA receptor. This chapter traces the translation of glycine reuptake inhibition therapy through the latest Phase III clinical trials of the potent selective GlyT1 inhibitor, bitopertin, developed by F. Hoffman-La Roche. We will explore the relevant neural mechanisms underlying this new pharmacotherapy, which appears to possess board spectrum efficacy against both positive and negative schizophrenia symptoms. Preclinical evidence suggests that GlyT1 inhibition may modulate multiple neurotransmitter pathways, including mesolimbic dopamine and brain glycinergic inhibition, which may provide new leads for further target refinement. Keywords Antipsychotic Bitopertin Glycine transporter N-methyl-d-aspartate receptor Schizophrenia
Original languageEnglish
Title of host publicationPsychiatry and Neuroscience Update
Subtitle of host publicationBridging the Divide
PublisherSpringer International Publishing
Pages353-374
Number of pages22
ISBN (Electronic)9783319171036
ISBN (Print)9783319171029
DOIs
Publication statusPublished - 1 Jan 2015

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)

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